tbuckley/cabot-search huggingface dataset:
Effective targeting of breast cancer by the inhibition of P-glycoprotein mediated removal of toxic lipid peroxidation byproducts from drug tolerant persister cells
Authors: Kornélia Szebényi, András Füredi, Eszter Bajtai, Sai Nagender Sama, Agnes Csiszar, Balázs Gombos, Pál Szabó, Michael Grusch, Gergely Szakács
Journal: Drug Resistance Updates (2023)

Therapy resistance has long been considered to occur through the selection of pre-existing clones equipped to survive and quickly regrow, or through the acquisition of mutations during chemotherapy. Here we show that following in vitro treatment by chemotherapy, epithelial breast cancer cells adopt a transient drug tolerant phenotype characterized by cell cycle arrest, epithelial-to-mesenchymal transition (EMT) and the reversible upregulation of the multidrug resistance (MDR) efflux transporter P-glycoprotein (P-gp). The drug tolerant persister (DTP) state is reversible, as cells eventually resume proliferation, giving rise to a cell population resembling the initial, drug-naïve cell lines. However, recovery after doxorubicin treatment is almost completely eliminated when DTP cells are cultured in the presence of the P-gp inhibitor Tariquidar. Mechanistically, P-gp contributes to the survival of DTP cells by removing reactive oxygen species-induced lipid peroxidation products resulting from doxorubicin exposure. In vivo, prolonged administration of Tariquidar during doxorubicin treatment holidays resulted in a significant increase of the overall survival of Brca1-/-;p53-/- mammary tumor bearing mice. These results indicate that prolonged administration of a P-gp inhibitor during drug holidays would likely benefit patients without the risk of aggravated side effects related to the concomitantly administered toxic chemotherapy. Effective targeting of DTPs through the inhibition of P-glycoprotein may result in a paradigm shift, changing the focus from countering drug resistance mechanisms to preventing or delaying therapy resistance.
Genetic Intratumor Heterogeneity Remodels the Immune Microenvironment and Induces Immune Evasion in Brain Metastasis of Lung Cancer
Authors: Xin Wang, Hua Bai, Jiyang Zhang, Zhijie Wang, Jianchun Duan, Hongqing Cai, Zheng Cao, Qingtang Lin, Xiaosheng Ding, Yiting Sun, Wei Zhang, Xiaoya Xu, Hao Chen, Dadong Zhang, Xiaoli Feng, Jinghai Wan, Jianjun Zhang, Jie He, Jie Wang
Journal: Journal of Thoracic Oncology (2023)

Brain metastasis, with the highest incidence in patients with lung cancer, significantly worsens prognosis and poses challenges to clinical management. To date, how brain metastasis evades immune elimination remains unknown.
Single‐cell RNA sequencing reveals the heterogeneity and intercellular communication of hepatic stellate cells and macrophages during liver fibrosis
Authors: Sheng Cheng, Yunhan Zou, Man Zhang, Shihao Bai, Kun Tao, Jiaoxiang Wu, Yi Shi, Yuelan Wu, Yinzhong Lu, Kunyan He, Peng Sun, Xianbin Su, Shangwei Hou, Bo Han
Journal: MedComm (2023)

Uncontrolled and excessive progression of liver fibrosis is thought to be the prevalent pathophysiological cause of liver cirrhosis and hepatocellular cancer, and there are currently no effective antifibrotic therapeutic options available. Intercellular communication and cellular heterogeneity in the liver are involved in the progression of liver fibrosis, but the exact nature of the cellular phenotypic changes and patterns of interregulatory remain unclear. Here, we performed single-cell RNA sequencing on nonparenchymal cells (NPCs) isolated from normal and fibrotic mouse livers. We identified eight main types of cells, including endothelial cells, hepatocytes, dendritic cells, B cells, natural killer/T (NK/T) cells, hepatic stellate cells (HSCs), cholangiocytes and macrophages, and revealed that macrophages and HSCs exhibit the most variance in transcriptional profile. Further analyses of HSCs and macrophage subpopulations and ligand-receptor interaction revealed a high heterogeneity characterization and tightly interregulated network of these two groups of cells in liver fibrosis. Finally, we uncovered a profibrotic Thbs1+ macrophage subcluster, which expands in mouse and human fibrotic livers, activating HSCs via PI3K/AKT/mTOR signaling pathway. Our findings decode unanticipated insights into the heterogeneity of HSCs and macrophages and their intercellular crosstalk at a single-cell level, and may provide potential therapeutic strategies in liver fibrosis.
Piperacillin-Tazobactam vs Cefoxitin Prophylaxis for Pancreatoduodenectomy
Authors: Ziyi Yang, Jiawei Mei, Wei Gong
Journal: JAMA (2023)

To the Editor A recent study1 found that antimicrobial prophylaxis with piperacillin-tazobactam was associated with lower rates of SSI and clinically relevant postoperative pancreatic fistula than cefoxitin in patients undergoing pancreatoduodenectomy.
Censorship of the Patient-Physician Relationship
Authors: Charles G. Kels
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Bone marrow fibrosis is associated with non‐response to <scp>CD19 CAR T</scp>‐cell therapy in <scp>B</scp>‐acute lymphoblastic leukemia
Authors: Joshua Anil, Ahab Alnemri, Andrew Lytle, Brian Lockhart, Ashley E. Anil, Michael Baumgartner, Kirubel Gebre, Jared McFerran, Stephan A. Grupp, Susan R. Rheingold, Vinodh Pillai
Journal: American Journal of Hematology (2023)

Abstract CD19 directed CAR T‐cell therapy is used to treat relapsed/refractory B‐cell acute lymphoblastic leukemia. The role of the pre‐CAR bone marrow (BM) stromal microenvironment in determining response to CAR T‐cell therapy has been understudied. We performed whole transcriptome analysis, reticulin fibrosis assessment and CD3 T‐cell infiltration on BM core biopsies from pre‐ and post‐CAR timepoints for 61 patients, as well as on a cohort of 54 primary B‐ALL samples. Pathways of fibrosis, extracellular matrix development, and associated transcription factors AP1 and TGF‐β3 , were enriched and upregulated in nonresponders (NR) even prior to CAR T cell therapy. NR showed significantly higher levels of BM fibrosis compared to complete responders by both clinical reticulin assessment and AI‐assisted digital image scoring. CD3+ T cells showed a trend toward lower infiltration in NR. NR had significantly higher levels of pre‐CAR fibrosis compared to primary B‐ALL. High levels of fibrosis were associated with lower overall survival after CAR T‐cell therapy. In conclusion, BM fibrosis is a novel mechanism mediating nonresponse to CD19‐directed CAR T‐cell therapy in B‐ALL. A widely used clinically assay for quantitating myelofibrosis can be repurposed to determine patients at high risk of non‐response. Genes and pathways associated with BM fibrosis are a potential target to improve response.
Screening for Hypertensive Disorders of Pregnancy
Authors: Michael J. Barry, Wanda K. Nicholson, Michael Silverstein, Michael D. Cabana, David Chelmow, Tumaini Rucker Coker, Esa M. Davis, Katrina E. Donahue, Carlos Roberto Jaén, Li Li, Gbenga Ogedegbe, Goutham Rao, John M. Ruiz, James Stevermer, Joel Tsevat, Sandra Millon Underwood, John B. Wong
Journal: JAMA (2023)

Importance Hypertensive disorders of pregnancy are among the leading causes of maternal morbidity and mortality in the US. The rate of hypertensive disorders of pregnancy has been increasing from approximately 500 cases per 10 000 deliveries in 1993 to 1021 cases per 10 000 deliveries in 2016 to 2017. Objective The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for hypertensive disorders of pregnancy. Population Pregnant persons without a known diagnosis of a hypertensive disorder of pregnancy or chronic hypertension. Evidence Assessment The USPSTF concludes with moderate certainty that screening for hypertensive disorders in pregnancy with blood pressure measurements has substantial net benefit. Recommendation The USPSTF recommends screening for hypertensive disorders in pregnant persons with blood pressure measurements throughout pregnancy. (B recommendation)
Screening for Hypertensive Disorders of Pregnancy
Authors: Jillian T. Henderson, Elizabeth M. Webber, Rachel G. Thomas, Kimberly K. Vesco
Journal: JAMA (2023)

Hypertensive disorders of pregnancy are a leading cause of pregnancy-related morbidity and mortality in the US.To conduct a targeted systematic review to update the evidence on the effectiveness of screening for hypertensive disorders of pregnancy to inform the US Preventive Services Task Force.MEDLINE and the Cochrane Central Register of Controlled Trials for relevant studies published between January 1, 2014, and January 4, 2022; surveillance through February 21, 2023.English-language comparative effectiveness studies comparing screening strategies in pregnant or postpartum individuals.Two reviewers independently appraised articles and extracted relevant data from fair-or good-quality studies; no quantitative synthesis was conducted.Morbidity or mortality, measures of health-related quality of life.The review included 6 fair-quality studies (5 trials and 1 nonrandomized study; N = 10 165) comparing changes in prenatal screening practices with usual care, which was routine screening at in-person office visits. No studies addressed screening for new-onset hypertensive disorders of pregnancy in the postpartum period. One trial (n = 2521) evaluated home blood pressure measurement as a supplement to usual care; 3 trials (total n = 5203) evaluated reduced prenatal visit schedules. One study (n = 2441) evaluated proteinuria screening conducted only for specific clinical indications, compared with a historical control group that received routine proteinuria screening. One additional trial (n = 80) only addressed the comparative harms of home blood pressure measurement. The studies did not report statistically significant differences in maternal and infant complications with alternate strategies compared with usual care; however, estimates were imprecise for serious, rare health outcomes. Home blood pressure measurement added to prenatal care visits was not associated with earlier diagnosis of a hypertensive disorder of pregnancy (104.3 vs 106.2 days), and incidence was not different between groups in 3 trials of reduced prenatal visit schedules. No harms of the different screening strategies were identified.This review did not identify evidence that any alternative screening strategies for hypertensive disorders of pregnancy were more effective than routine blood pressure measurement at in-person prenatal visits. Morbidity and mortality from hypertensive disorders of pregnancy can be prevented, yet American Indian/Alaska Native persons and Black persons experience inequitable rates of adverse outcomes. Further research is needed to identify screening approaches that may lead to improved disease detection and health outcomes.
Xuebijing Injection for Sepsis Treatment: When Will It Be Approved Outside of China?—Reply
Authors: Songqiao Liu, Jianfeng Xie, Haibo Qiu
Journal: JAMA Internal Medicine (2023)

In Reply We appreciate Dr Hu's interest in and thoughtful criticism of our clinical trial.1 We agree that it will be challenging to get Xuebijing approved outside of China, but that the obstacles are surmountable.2
Mitochondrial-targeted brequinar liposome boosted mitochondrial-related ferroptosis for promoting checkpoint blockade immunotherapy in bladder cancer
Authors: Qiubo Ding, Weinan Tang, Xianglong Li, Yuanzhen Ding, Xinnan Chen, Wenmin Cao, Xinwu Wang, Wenjing Mo, Zhigui Su, Qing Zhang, Hongqian Guo
Journal: Journal of Controlled Release (2023)
Suppression of Tumor Cell Lactate-generating Signaling Pathways Eradicates Murine PTEN/p53-deficient Aggressive-variant Prostate Cancer via Macrophage Phagocytosis
Authors: Kiranj Chaudagar, Hanna M. Hieromnimon, Anne Kelley, Brian Labadie, Jordan Shafran, Srikrishnan Rameshbabu, Catherine Drovetsky, Kaela Bynoe, Ani Solanki, Erica Markiewicz, Xiaobing Fan, Massimo Loda, Akash Patnaik
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Phosphatase and tensin homolog (PTEN) loss-of-function/PI3K pathway hyperactivation is associated with poor therapeutic outcomes and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies in Pb-Cre;PTENfl/flTrp53fl/fl genetically engineered mice (GEM) with aggressive-variant prostate cancer (AVPC) demonstrated tumor growth control in 60% mice following androgen deprivation therapy/PI3K inhibitor (PI3Ki)/programmed cell death protein 1 (PD-1) antibody combination, via abrogating lactate cross-talk between cancer cells and tumor-associated macrophages (TAM), and suppression of histone lactylation (H3K18lac)/phagocytic activation within TAM. Here, we targeted immunometabolic mechanism(s) of PI3Ki resistance, with the goal of durable tumor control in AVPC. Experimental Design: Pb-Cre;PTENfl/flTrp53fl/fl GEM were treated with PI3Ki (copanlisib), MEK inhibitor (trametinib) or Porcupine inhibitor (LGK'974) singly or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo coculture mechanistic studies were performed on GEM tumors or corresponding tumor-derived cell lines. Results: Given our proteomic profiling showing persistent MEK signaling within tumors of PI3Ki-resistant GEM, we tested whether addition of trametinib to copanlisib enhances tumor control in GEM, and we observed 80% overall response rate via additive suppression of lactate within TME and H3K18lac within TAM, relative to copanlisib (37.5%) monotherapy. The 20% resistant mice demonstrated feedback Wnt/β-catenin activation, resulting in restoration of lactate secretion by tumor cells and H3K18lac within TAM. Cotargeting Wnt/β-catenin signaling with LGK'974 in combination with PI3Ki/MEKi, demonstrated durable tumor control in 100% mice via H3K18lac suppression and complete TAM activation. Conclusions: Abrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials.
Role of dopamine in the pathophysiology of Parkinson’s disease
Authors: Zhi Dong Zhou, Ling Xiao Yi, Dennis Qing Wang, Tit Meng Lim, Eng King Tan
Journal: Translational Neurodegeneration (2023)

A pathological feature of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars compacta in PD brains. DA is the neurotransmitter of dopaminergic neurons. Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology. Disturbances of DA synthesis, storage, transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models. DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products, including reactive oxygen species, DA quinones, and 3,4-dihydroxyphenylacetaldehyde. Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways, and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA.
School-Based Health Centers, Access to Care, and Income-Based Disparities
Authors: Michel Boudreaux, Jun Chu, Brandy J. Lipton
Journal: JAMA Network Open (2023)

School-based health centers (SBHCs) are primary care clinics colocated at schools. SBHCs have the potential to improve health care access and reduce disparities, but there is limited rigorous evidence on their effectiveness at the national level.
Outcomes in Patients With Poststroke Seizures
Authors: Shubham Misra, Scott E. Kasner, Jesse Dawson, Tomotaka Tanaka, Yize Zhao, Hitten P. Zaveri, Ece Eldem, Juan Vazquez, Lucas Scárdua Silva, Saba Mohidat, L. Brian Hickman, Erum I. Khan, Melissa C. Funaro, John-Paul Nicolo, Rajarshi Mazumder, Clarissa Lin Yasuda, Katharina S. Sunnerhagen, Masafumi Ihara, Joseph S. Ross, David S. Liebeskind, Patrick Kwan, Terence J. Quinn, Jerome Engel, Nishant K. Mishra
Journal: JAMA Neurology (2023)

Published data about the impact of poststroke seizures (PSSs) on the outcomes of patients with stroke are inconsistent and have not been systematically evaluated, to the authors' knowledge.
Seat Belt Use in the US by Pregnant Motor Vehicle Occupants
Authors: Corina Espelien, Ruyun Jin, Susan Mostofizadeh, Rachel VanRyzin, Thomas Hartka, Jason Forman, Pavel Chernyavskiy
Journal: JAMA Network Open (2023)

This cross-sectional study assesses patterns of seat belt use among pregnant, nonpregnant, and male occupants.
Human papillomavirus vaccination and anal high-grade precancerous lesions and cancer—a real-world effectiveness study
Authors: Louise Baandrup, Thomas Maltesen, Christian Dehlendorff, Susanne K Kjaer
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Human papillomavirus (HPV) vaccination has shown high efficacy against anal HPV infection and lesions in clinical trials, and the HPV prevalence and type distribution in anal precancers and cancer predict a high preventable potential for HPV vaccination. However, the real-world effectiveness of HPV vaccination against anal high-grade lesions and cancer is yet to be shown. Methods We investigated HPV vaccine effectiveness against anal high-grade squamous intraepithelial lesion (HSIL) or worse in a nationwide cohort including all Danish women aged 17-32 years during October 2006 to December 2021 (n = 968 881). HPV vaccinations and first occurrence of anal HSIL or worse were retrieved from nationwide registries. Women were considered vaccinated after first dose and classified by age at vaccination. Using Cox regression, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for anal HSIL or worse according to vaccination status. Results During follow-up, the number of incident histological anal HSIL or worse cases was 37 in unvaccinated women, and less than 5 and 26 in women vaccinated at ages younger than 17 years and 17-32 years, respectively. The overall number of cancers was less than 5. Compared with unvaccinated women, the risk of histological anal HSIL or worse was reduced for women vaccinated at age younger than 17 years (HR = 0.30, 95% CI = 0.10 to 0.87). For women vaccinated at age 17-32 years, the hazard rate of anal HSIL or worse was 1.21 (95% CI = 0.73 to 2.03). Conclusion This is the first study to demonstrate that HPV vaccination at a younger age is associated with substantially reduced risk of anal HSIL or worse in the general population.
Hyperglycemia and insulin infusion in pancreatoduodenectomy: a prospective cohort study on feasibility and impact on complications
Authors: Eva Ekström, Katarina Fagher, Bobby Tingstedt, Jenny Rystedt, Johan Nilsson, Magnus Löndahl, Bodil Andersson
Journal: International Journal of Surgery (2023)

Background: Hyperglycemia is a risk factor for postoperative complications but its impact on outcome after pancreatoduodenectomy (PD) is scarcely studied. This prospective cohort study aimed to assess the effect of continuous insulin infusion on postoperative complications and blood glucose, as well as to evaluate the impact of hyperglycemia on complications, after PD. Materials and methods: One hundred patients planned for PD were prospectively included for perioperative continuous insulin infusion and a historic cohort of 100 patients was included retrospectively. Median blood glucose levels were calculated and data on complications were analyzed and compared between the historic cohort and the intervention group as well as between normo- and hyperglycemic patients. Results: Median glucose levels were significantly lower in the intervention group compared to the historic cohort up to 30 days postoperatively (median glucose 8.5 mmol/l (IQR 6.4 – 11) vs. 9.1 mmol/l (IQR 6.8 – 17) ( P =0.007)). No significant differences in complication rates were recorded between these two groups. The incidence of complications classified as Clavien ≥3 was higher in hyperglycemic patients (100% vs. 27%, P =0.024). Among hyperglycemic patients the prevalence of preoperative diabetes was higher compared to normoglycemic patients (52% vs.12%, P &lt;0.001). In patients with a known diagnosis of diabetes, a trend, although not statistically significant, towards a lower incidence of postoperative pancreatic fistula (POPF) grade B and C, as well as postpancreatectomy hemorrhage (PPH) grade B and C, was seen compared to those without preoperative diabetes (6.8% vs. 14%, P =0.231 and 2.3% vs. 7.0%, P =0.238 respectively). Conclusion: Insulin infusion in the early postoperative phase after PD is feasible in a non-ICU setting and significantly decreased blood glucose levels. The influence on complications was limited. Preoperative diabetes was a significant predictor of postoperative hyperglycemia and was associated with a lower incidence of clinically significant POPF.
Declines in Wealth Among US Older Adults at Risk of Dementia
Authors: Jing Li, Jonathan S. Skinner, Kathleen McGarry, Lauren Hersch Nicholas, Shao-Pang Wang, Evan Bollens-Lund, Amy S. Kelley
Journal: JAMA Neurology (2023)

This case-control study uses Health and Retirement Study data to examine the trajectories of wealth among US older adults at risk of dementia.
Piperacillin-Tazobactam vs Cefoxitin Prophylaxis for Pancreatoduodenectomy—Reply
Authors: Ryan J. Ellis, Clifford Y. Ko, Michael I. D’Angelica
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal